PROJECT SUMMARY/ABSTRACT Obesity-driven metabolic dysfunction is a driver of cardiovascular disease, type II diabetes, fatty liver disease, thrombosis, and numerous cancers, and thus underlies substantial morbidity and mortality in the United States. In obese humans with metabolic syndrome, and in mouse models of obesity, pathologic outcomes are driven by a chronic inflammatory state of ?metabolic inflammation,? in which immune cells (eg, macrophages) and immune modulators (eg, cytokines) hijack normal metabolic function. Coagulation cascade activation is a conspicuous feature of obesity in humans and is similarly prominent in high fat diet (HFD)-challenged mice. Compelling published and new findings from our research team suggest that fibrin deposits in adipose are an important, yet largely unappreciated driver of metabolic inflammation, and a powerful determinant of adipose and liver pathologies in the obese state. The scientific premise for the proposed research is that fibrin(ogen), factor XIII (fXIII), and ?2 integrins have all independently been implicated in the pathogenesis of obesity sequelae in experimental obesity. However, the precise mechanism(s) by which fibrin promotes inflammation, including the molecular form of the molecule and the precise cell-surface receptors mediating inflammatory cell activities, remains largely undefined. The central hypothesis framing these studies is that stabilized extravascular fibrin deposits in adipose exacerbate macrophage-mediated metabolic inflammation by engaging leukocyte integrin receptors ?M?2 and ?X?2. The principal objective of this study is to determine the mechanisms whereby shifts in fibrinogen deposits in adipose and liver trigger local inflammatory cell activation and dysfunctional metabolism in experimental obesity Specifically, we will: (i) determine whether the conversion of fibrinogen to crosslinked fibrin matrices and the engagement of the leukocyte integrin receptor ?M?2 are mechanistically coupled to the development of diet-induced obesity and metabolic dysfunction (AIM1); (ii) determine the contribution of immobilized fibrinogen, fibrin, and crosslinked fibrin to ?2 integrin-dependent changes in macrophage phenotype as well as macrophage-mediated adipogenesis and lipid accumulation within cells (AIM2); and (iii) determine the systemic and tissue-based changes in metabolism (specifically glucose handling) mediated by fibrin(ogen). (AIM3). The insights gained will significantly advance the current understanding of obesity development and highlight novel therapeutic opportunities centering on fibrin(ogen) in the treatment of obesity-driven metabolic pathologies.